Daily Ards Research Analysis
An RCT of transvenous diaphragm neurostimulation showed a high posterior probability of improving 30-day weaning success and shortening ventilation, albeit with more serious adverse events. A large prospective post-mortem biopsy cohort clarified that diffuse alveolar damage dominates fatal COVID-19 ARDS and that corticosteroid-sensitive patterns (OP/AFOP) are common. Human genetic PheWAS suggests a favorable systemic profile for TRPC6 inhibition, informing therapeutic development relevant to ARD
Summary
An RCT of transvenous diaphragm neurostimulation showed a high posterior probability of improving 30-day weaning success and shortening ventilation, albeit with more serious adverse events. A large prospective post-mortem biopsy cohort clarified that diffuse alveolar damage dominates fatal COVID-19 ARDS and that corticosteroid-sensitive patterns (OP/AFOP) are common. Human genetic PheWAS suggests a favorable systemic profile for TRPC6 inhibition, informing therapeutic development relevant to ARDS.
Research Themes
- Ventilator weaning interventions
- Pathologic mechanisms in fatal COVID-19 ARDS
- Genetic target validation for ARDS-relevant therapeutics
Selected Articles
1. Temporary Transvenous Diaphragm Neurostimulation for Weaning from Mechanical Ventilation (RESCUE-3).
In an open-label, multicenter RCT with Bayesian primary analysis, twice-daily transvenous diaphragm neurostimulation increased the probability of 30-day weaning success (HR 1.34; posterior probability 97.9%) and tended to shorten ventilation by 2.5 days. Serious adverse events were more frequent in the treatment group, with no clear mortality difference.
Impact: This is the first international RCT to test transvenous diaphragm neurostimulation for difficult weaning, using a prespecified Bayesian framework and clinically meaningful endpoints.
Clinical Implications: For patients ventilated ≥96 hours with repeated weaning failures, transvenous diaphragm neurostimulation could be considered as an adjunct to enhance weaning success, but requires careful monitoring given higher serious adverse events and confirmation in larger, blinded trials.
Key Findings
- 30-day weaning success was higher with neurostimulation (70% vs 61%; adjusted HR 1.34; 95% CrI 1.01–1.78; posterior superiority 97.9%).
- Ventilation duration to Day 30 was reduced by a mean of 2.5 days (95% CrI −5.0 to 0.1; posterior superiority 97.1%).
- Serious adverse events occurred more frequently in the treatment group (36% vs 24%); mortality was similar (9.8% vs 10.5%).
Methodological Strengths
- International, multicenter randomized design with prespecified Bayesian analysis borrowing prior data.
- Clinically meaningful endpoints (weaning success, ventilation duration, mortality) and modified intent-to-treat population.
Limitations
- Open-label design and early termination may bias estimates and limit statistical power.
- Higher rate of serious adverse events in the treatment arm requires careful interpretation and mechanistic understanding.
Future Directions: Conduct adequately powered, blinded RCTs to confirm efficacy, refine patient selection, and optimize stimulation protocols while characterizing safety mechanisms.
2. Post-mortem lung biopsies in fatal Covid-19 acute respiratory distress syndrome: a prospective cohort study of 169 patients (HISTOCOVID).
In 169 fatal COVID-19 ARDS cases, bedside post-mortem percutaneous lung biopsies showed diffuse alveolar damage predominating, mainly in proliferative phases, with relatively rare collagen fibrosis and microthrombi. Notably, OP/AFOP patterns were present in about one quarter, suggesting a potential role for intensified or prolonged corticosteroids in selected refractory cases.
Impact: This is a large, prospective, multicenter pathologic study using standardized bedside post-mortem biopsies, clarifying dominant lung injury patterns in fatal COVID-19 ARDS and revealing steroid-responsive lesions.
Clinical Implications: Pathological predominance of proliferative-phase DAD with frequent OP/AFOP supports considering corticosteroid optimization (dose/duration) in carefully selected refractory COVID-19 ARDS patients, and refocuses therapeutic targets on lung repair and inflammation rather than microthrombosis.
Key Findings
- Diffuse alveolar damage was the predominant pattern: early proliferative (39%), late proliferative (32%), exudative (18%), fibrotic (2%).
- OP and AFOP were identified in 13% and 9% of patients, respectively.
- Microthrombi were uncommon (6%), and collagen fibrosis was rare at death.
Methodological Strengths
- Prospective, multicenter cohort with standardized bedside post-mortem percutaneous biopsy protocol.
- Centralized pathological assessment with comprehensive lesion cataloging.
Limitations
- Needle biopsy sampling may miss heterogeneous lesions and under-represent microthrombi.
- Post-mortem timing and COVID-19–specific context limit generalizability to non-COVID ARDS or earlier disease stages.
Future Directions: Correlate pathologic phenotypes with premortem clinical trajectories and response to corticosteroids; evaluate targeted anti-inflammatory and repair-promoting therapies in DAD versus OP/AFOP-enriched phenotypes.
3. Genetic exploration of targeting the transient receptor potential cation channel subfamily member 6.
Using eQTL-driven PheWAS in 475,739 UK Biobank participants, genetically mediated lower TRPC6 expression was significantly associated with reduced coronary artery disease and atrial fibrillation risk after multiple-testing correction. Nominal associations suggested both potential benefits and risks, with no clearly deleterious phenotypes, supporting a favorable systemic profile for TRPC6 inhibition.
Impact: Human genetics provides system-wide safety-efficacy signals for TRPC6 inhibition, informing drug development across organs, including ARDS indications under investigation.
Clinical Implications: TRPC6 inhibitors may have a favorable systemic profile; clinical trials should proceed with monitoring for venous thromboembolism and hypertension while leveraging potential cardiovascular benefits. For ARDS, these data support continued evaluation of TRPC6-targeted strategies.
Key Findings
- Genetically reduced TRPC6 expression was significantly associated with lower risk of coronary artery disease and atrial fibrillation after multiple-testing correction.
- Nominal associations indicated reduced anxiety, heart failure, and stroke risk, but increased venous thromboembolism, hypertension, appendicitis, and liver cirrhosis risk.
- No clearly deleterious phenotypes emerged, suggesting a favorable systemic profile for TRPC6 inhibition.
Methodological Strengths
- Very large sample size (n=475,739) with phenome-wide assessment across 64 phenotypes and multiple organ systems.
- Use of genetic proxies for TRPC6 expression (eQTL-based) reduces confounding and supports causal inference hypotheses.
Limitations
- Observational genetic associations cannot fully mimic pharmacologic inhibition; pleiotropy may bias estimates.
- Cross-sectional PheWAS lacks temporal resolution and does not directly assess ARDS outcomes.
Future Directions: Integrate Mendelian randomization and functional studies to dissect causality; prospectively monitor safety signals (e.g., VTE, hypertension) in TRPC6 inhibitor trials, including ARDS indications.